Rufei Lu, MD, PhD
2022 Recipient of the Gary S. Gilkeson Career Development Award
The Regents of the University of California, San Francisco
Title of Project: Understanding pathogenesis of neuropsychiatric lupus
Mentor: Eric J. Huang, MD, PhD
About the Researcher
I received my M.D./PhD training from the Department of Pathology at the University of Oklahoma Health Sciences Center and the Arthritis and Clinical Immunology Research Program at Oklahoma Medical Research Foundation (OMRF). After graduating in 2017, I completed a combined Anatomic Pathology/Clinical Pathology residency in the Department of Pathology at OUHSC. My Ph.D. thesis studied the pathogenesis of systemic lupus erythematosus (SLE) and delineated clinical courses of this autoimmune disease. SLE is a complex and prototypical autoimmune disease with a wax-wane clinical course in most patients. Understanding the early events and triggers in the preclinical period furthers our knowledge in SLE pathogenesis and provides potential therapies for disease prevention. As part of my graduate work, I studied the effects of vitamin D deficiency in the early development of SLE and functions of several SLE- associated genes, including BLK and BANK1. However, organ damages do not occur immediately after the development of autoimmunity but rather accumulate over time through multiple disease flares. In the hope of halting the autoimmunity-induced damages, I also studied the mechanism of disease flares and have written Random Forest Machine Learning based algorithms to predict the onset of disease flare. While in residency, I continued my research at OMRF to understand the mechanism of disease flare and develop accurate prediction models for SLE flares based on peripheral soluble mediators. In addition to the mechanism of disease flare research, I also developed an interest in neuropathology and neuroinflammation, particularly neuropsychiatric manifestations of SLE (NPSLE). While neuropsychiatric manifestations (NPSLE) account for a considerable portion of SLE clinical presentations and contribute significantly to SLE mortality and morbidity, the pathogenesis of NPSLE remains unclear. Furthermore, as a family member of an SLE patient who had NPSLE, I am committed to pursuing a career to understand the pathogenesis of NPSLE, develop reliable diagnostic assays, and advance therapeutic development. To this end, I joined the renowned neuropathology fellowship at the University of California, San Francisco, to further my training in neuropathology. As a postdoctoral fellow in Dr. Huang’s laboratory, I will focus on the interaction between autoimmune dysfunction, neuroinflammation, and neurodegeneration. My goal is to leverage the autoimmune dysfunction in a highly reproducible mouse model for frontotemporal lobar degeneration (FTLD) and dissect how autoantibodies promote glial activation and neuronal degeneration using the iPSC-derived model systems.
Systemic lupus erythematosus (SLE) is an incurable chronic condition that occurs when a person’s immune system attacks their own organs. SLE can present with various symptoms, including acute confusional state, anxiety/mood disorders, and even psychosis. SLE patients are also more likely to develop dementia when compared to the general population. Despite the ongoing efforts, the precise cause of these neurological symptoms is not well-understood. A major obstacle to studying these symptoms is that we rarely biopsy the brain and do not have a dedicated animal model. To overcome this challenge, we plan to use a newly described mouse model that mimics what happens in SLE patients with neurological symptoms to study the disease.
To simulate what happens in our body in a controlled laboratory setting, we will first make pluripotent stem cells (iPSC), which are cells that can potentially become cells found in our brains. Then we can use these cells to make replenishable mixtures of cells normally found in the brains in the laboratory, so we do not have to use biopsied tissue from SLE patients or mice. Once we can make these laboratory mimickers of brains (ex vivo models), we can study how the immune cells from the mice’s blood affect and damage these brain cells by adding blood from the mice at different stages of their disease to these ex vivo models. We will analyze multiple parameters that affect the immune cells’ functions to see how these altered functions can lead to downstream damages in different types of cells in the brain. After we better understand how altered immune cells can affect the brain in mice, we will confirm the findings in humans by using the similar technology as described above. Instead, we will make these ex vivo models from the blood from the SLE patients with neurological symptoms and add patients’ blood to these models to monitor the changes.
An enhanced understanding of how diseased immune cells attack the cells in the brain and the proven feasibility of iPSC-derived ex vivo models will pave the way for future studies and the development of potential therapies for SLE patients with neurological symptoms.